Project Summary/Abstract African American (AA) women have higher breast cancer mortality rates compared to other races. A greater prevalence of basal-like breast cancers in AA women explain some disparities, as these tumors are clinically the most aggressive, characterized by cancer stem No effective therapies exist and cell features. survival is poor. Escalating this disparity is the disease promoting effects of obesity, which is significantly higher in AA. The majority of studies on breast cancer disparities examine tumor characteristics, but the etiologic factors that lead to this disparity remain undefined. Our primary objective is to identify the mechanisms involved in promoting aggressive breast cancer in AAs, as a consequence of stromal effects at the site of the cancerous lesion. A key molecular pathway has been identified which integrates these clinical, microenvironmental and biological factors to affect tumor behavior. Aim 1 takes a novel approach, combining our published proteomic and gene expression datasets detailing race and tumor-subtype specific stromal interactions with our recently published data on the identified pathway promoting cancer stem cell- like, aggressive behaviors. Aims 2 and 3 extend these data to experimental studies to elucidate mechanistic details. To accomplish these tasks, our team established research partnerships that provides access to resources including the Normal Breast Study: a unique epidemiologic study from ethnically diverse patients at UNC Hospitals. There are several important biological implications of this work. The observation that AA breast tissue is enriched with distinct proteins, the prevalence of obesity in AA, and the predisposition to develop basal-like tumors strongly suggests a biological link between race, metabolism and cancer subtype. The role of differentially regulated metabolic-sensitive proteins in the tumor microenvironment will provide novel insights into the biological basis of racial disparities. The long-term goal of our collaboration is to understand tumor-microenvironment interactions and their influence on breast cancer disparities. Our distinctive approach will expose unique characteristics of the breast tissue microenvironment and will integrate advances in the field of tumor microenvironment with health disparities research. Relevance This proposal addresses breast cancer disparities by studying a key pathway that drive the aggressiveness of breast cancers. By combining observational studies on differences in this pathway by race, BMI, and breast cancer subtype with experimental studies to understand the role of this pathway in cellular phenotypes, this project will provide important and novel insight into the biological basis of racial disparities.